Heart failure impairs the mechanotransduction propeties of human cardiac pericytes,Journal of Molecular and Cellular Cardiology

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Heart failure impairs the mechanotransduction propeties of human cardiac pericytes
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-11-05 , DOI: 10.1016/j.yjmcc.2020.10.016
Irene Giulia Rolle ₁ , Ilaria Crivellari ₁ , Andrea Zanello ₁ , Elisa Mazzega ₁ , Emiliano Dalla ₁ , Michela Bulfoni ₁ , Elisa Avolio ₂ , Alice Battistella ₃ , Marco Lazzarino ₃ , Alice Cellot ₁ , Celeste Cervellin ₁ , Sandro Sponga ₄ , Ugolino Livi ₅ , Nicoletta Finato ₆ , Gianfranco Sinagra ₇ , Aneta Aleksova ₇ , Daniela Cesselli ₆ , Antonio Paolo Beltrami ₁

Affiliation

The prominent impact that coronary microcirculation disease (CMD) exerts on heart failure symptoms and prognosis, even in the presence of macrovascular atherosclerosis, has been recently acknowledged. Experimental delivery of pericytes in non-revascularized myocardial infarction improves cardiac function by stimulating angiogenesis and myocardial perfusion.

Aim of this work is to verify if pericytes (Pc) residing in ischemic failing human hearts display altered mechano-transduction properties and to assess which alterations of the mechano-sensing machinery are associated with the observed impaired response to mechanical cues.

Results

Microvascular rarefaction and defects of YAP/TAZ activation characterize failing human hearts. Although both donor (D-) and explanted (E-) heart derived cardiac Pc support angiogenesis, D-Pc exert this effect significantly better than E-Pc. The latter are characterized by reduced focal adhesion density, decreased activation of the focal adhesion kinase (FAK)/ Crk-associated substrate (CAS) pathway, low expression of caveolin-1, and defective transduction of extracellular stiffness into cytoskeletal stiffening, together with an impaired response to both fibronectin and lysophosphatidic acid. Importantly, Mitogen-activated protein kinase kinase inhibition restores YAP/TAZ nuclear translocation.

Conclusion

Heart failure impairs Pc mechano-transduction properties, but this defect could be reversed pharmacologically.

中文翻译：

心力衰竭损害人类心脏周细胞的机械转导特性

冠状动脉微循环疾病 (CMD) 对心力衰竭症状和预后的显着影响，即使在存在大血管动脉粥样硬化的情况下，最近也得到了承认。在非血运重建心肌梗死中实验性递送周细胞通过刺激血管生成和心肌灌注来改善心脏功能。

这项工作的目的是验证驻留在缺血性衰竭人类心脏中的周细胞 (Pc) 是否显示出改变的机械转导特性，并评估机械传感机制的哪些改变与观察到的对机械线索的反应受损有关。

结果

YAP/TAZ 激活的微血管稀疏和缺陷是人类心脏衰竭的特征。尽管供体 (D-) 和外植 ( E- ) 心脏衍生的心脏 Pc 都支持血管生成，但 D-Pc 的这种作用明显优于 E-Pc。后者的特点是粘着斑密度降低、粘着斑激酶 (FAK)/Crk 相关底物 (CAS) 通路的激活减少、caveolin-1 的低表达以及细胞外僵硬转导到细胞骨架硬化的缺陷，以及对纤连蛋白和溶血磷脂酸的反应受损。重要的是，丝裂原活化蛋白激酶激酶抑制恢复 YAP/TAZ 核易位。